Vascular Remodeling Process in Pulmonary Arterial Hypertension, with Focus on miR‐204 and miR‐126 (2013 Grover Conference Series)

Abstract

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized primarily by increased proliferation and resistance to apoptosis in distal pulmonary arteries. Previous literature has demonstrated that the transcription factors NFAT (nuclear factor of activated T cells) and HIF-1α (hypoxia inducible factor 1α) are extensively involved in the pathogenesis of this disease and, more recently, has implicated STAT3 (signal transducer and activator of transcription 3) in their activation. Novel research shows that miR-204, a microRNA recently found to be notably downregulated through induction of PARP-1 (poly [ADP-ribose] polymerase 1) by excessive DNA damage in PAH, inhibits activation of STAT3. Contemporary research also indicates systemic impairment of skeletal muscle microcirculation in PAH and attributes this to a debilitated vascular endothelial growth factor pathway resulting from reduced miR-126 expression in endothelial cells. In this review, we focus on recent research implicating miR-204 and miR-126 in vascular remodeling processes, data that allow a better understanding of PAH molecular pathways and constitute a new hope for future therapy.Keywords: pulmonary arterial hypertension, microRNA, vascular remodeling, angiogenesis, skeletal muscle. Pulmonary arterial hypertension (PAH) is a severe disorder clinically defined by mean pulmonary arterial pressure of at least 25 mmHg at rest. 1 PAH patients display multiple symptoms that are not specific to PAH, including dyspnea, dizziness, and exercise intolerance. Mean age at diagnosis is around 45 years, although onset of symptoms can occur at any age. 2 Epidemiologically, it is estimated that between 20 and 50 persons per million suffer from this disease. 3 Physiologically, PAH is a vascular remodeling disease of various degrees that affects the adventitia, media, and intima of distal pulmonary arteries, leading to decreased lung perfusion and sustained elevation of pulmonary vascular resistance. 4 In response to this resistance, patients develop progressive compensatory right ventricular hypertrophy, which rapidly becomes insufficient and leads to dilatation and failure. 5,6 Histologically, PAH is associated with enhanced inflammation, proliferation, and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs). 7 Despite progress in treatment, medication remains limited and noncurative, and therefore PAH patients typically have poor prognoses (mortality rate of more than 10% after the first year of therapy) 8 and quality of life remains severely affected. The pathological mechanisms of PAH establishment need to be better understood and further studied because of their complexities and therapeutic interest. Indeed, knowledge regarding the molecular actors implicated in these impairments increases with each publication, revealing a complex process that remains far from being completely understood.In the past few years, literature has consistently implicated the role of microRNAs (miRNAs) in PAH. Briefly, miRNAs are s...

Molecular mechanisms in vascular injury induced by hypertension: Expression and role of microRNA‑34a

“…For instance, miR-122 induced endothelial NO metabolic disorder and disrupted diastolic and contractile function of the vascular endothelium by targeting solute carrier family 7 member 1, leading to the development of primary hypertension (21). Furthermore, miR-204 may be involved in vascular remodeling by regulating the proliferation and apoptosis of vascular smooth muscle cells (22). In addition, a number of other miRNAs have been associated with hypertension, including miR-296-5p, let-7e, miR-15b and miR-185, and their roles in regulating the development of hypertension require further investigation (23).…”

The master switchers in the aging of cardiovascular system, reverse senescence by microRNA signatures; as highly conserved molecules

“…Modulating PARP-1 activation protects against hypertrophy response, heart failure, and cardiovascular dysfunction (Yao and Ventura, 2011). PARP1 is linked directly to cellular redox status and oxidative stress by regulating FOXO, the stress resistance TF which extends lifespan in Caenorhabditis elegans Canto and Auwerx, 2011;Potus et al, 2014;Kim et al, 2014).…”

“…DDR/telomere erosion damps mitochondrial function through decreasing the activity of SIRT1/PGC-1a, a master transcriptional regulatory pathway in mitochondrial biogenesis and activity versus p53. This new pathway involves specially the inside interplay of SIRT1/PARP1 system (Pacher and Szabo, 2007;Canto and Auwerx, 2011;Potus et al, 2014).…”

“…In response to oxidative stress and inflammatory injury, DNA repair involves PARP1 activity to recruit and assemble the components of DDR machinery, but its over-activation in a feed-forward loop manner can eventually confront SIRT1 activation (Canto and Auwerx, 2011;Potus et al, 2014;Kim et al, 2014).…”

“…Otherwise upon PARP overactivation, cells undergo apoptosis due to over-expression of senescence-associated (SA) miRNAs such as miRNA-34a through p53 activation. There is a double-positive feedback loop between SA-miRNAs over-expression and PARP over-activation (Canto and Auwerx, 2011;Potus et al, 2014;Kim et al, 2014).…”